5.7 million neonatal deaths and stillbirths: infections, organisms and measurement black holes
Professor Joy Lawn FMedSci, London School of Hygiene & Tropical Medicine, UK
Of the annual 2.7 million neonatal deaths, the most recent estimates for 196 countries suggest that neonatal infections causes approximately 600,000 deaths, almost double the number of child deaths from malaria plus HIV/AIDS. Yet for neonatal infections (apart from tetanus) there is much slower mortality reduction, and very limited global health investment. If the closely linked burden of 2.6 million stillbirths could be accurately assessed for infection, and the impairment outcomes for survivors of neonatal infection were included then the associated burden would be even more striking.
There are measurement black holes which impede evidence based investment and faster reduction of this burden, but could be targeted. For example, new analysis shows the important contribution of group B streptococcus to stillbirths, as well as neonatal invasive disease, with implications for cost-effectiveness of maternal vaccination. Some of the most important measurement black holes regarding neonatal infections will be detailed, highlighting opportunities for change, notably the following: aetiological data, stillbirth investigations including infection aetiology, impairment outcomes for survivors of neonatal infections, and measuring the coverage and quality of care.
Gram-negative bacterial infections in the neonate – global epidemiology
Dr Julia Bielicki, St George's, University of London, UK
Gram-negative bacterial infections, in particular sepsis caused by Gram-negative bacteria, can have devastating consequences during the neonatal period. Rising levels of antimicrobial resistance among Gram-negative bacteria globally are an additional cause for concern, as therapeutic options are limited. In particular, data from lower and middle income countries, where neonates experience a high burden of infections with considerable associated mortality and morbidity, demonstrate that many Gram negative isolates are resistant to both first- and second-line empiric regimens recommended by the World Health Organization. Furthermore, there are a number of reports of outbreaks caused by multidrug resistant Gram-negative bacteria in the setting of neonatal inpatient care. It has been estimated that up to 30% of neonatal deaths due to sepsis are attributable to multi-drug resistant bacteria, with extended-spectrum beta-lactamase producing Gram negative bacteria being among the main culprits. However, available surveillance data is of insufficient quality to gain robust insights into the global epidemiology of neonatal Gram-negative bacterial infections. Improved and integrated surveillance is necessary to identify the areas of greatest therapeutic need in this population. Currently available antibiotic treatment options are limited, and the potential effectiveness of other interventions has not been sufficiently studied. Alternative interventions range from non-invasive attempts to influence the colonising microflora (for example through increased mother-baby skin-to-skin contact) to the prophylactic use of monoclonal antibodies against key bacteria.
Group B Streptococcal disease and neonatal susceptibility to infection
Professor Philipp Henneke, Center for Pediatrics and Center for Chronic Immunodeficiency, University of Freiburg, Germany
Neonatal group B streptococcal sepsis is a highly inflammatory disease, where bacterial effectors induce cytokines leading to end organ failure, long term sequels and lethality. We have identified the interaction of streptococcal RNA and lipopeptides with Toll-like receptors and cytosolic sensors as key molecular events in this process. Moreover, tissue specific changes in immune cell composition under influence of the emerging microbiota substantially contribute to susceptibility to infection and course of the disease. Accordingly, manipulation of the site specific innate immune cell response on the cognate receptor level is a rational strategy for improving outcome in group B streptococcal sepsis.
Global burden of congenital CMV infection
Professor Suresh Boppana, University of Alabama School of Medicine, USA
Cytomegalovirus (CMV) is a leading cause of congenital infection worldwide. In the developed world, it is a leading non-genetic cause of childhood hearing loss and neurodevelopmental disabilities. The prevalence of congenital CMV infection is directly related to CMV seroprevalence in women of child-bearing age. Therefore, the populations in the developing world experience the higher prevalence of congenital CMV infection (1-5% of births) and are most likely driven by non-primary maternal infections. Although reliable estimates of prevalence and outcome from different regions of the world are not available, recent data demonstrating similar rates of hearing loss following primary and non-primary maternal infection have underscored the importance of congenital CMV infection in resource-poor settings. Therefore, successful implementation of strategies to prevent or reduce the burden of congenital CMV infection will require heightened global awareness among clinicians and the general population and a better understanding of the factors associated with intrauterine transmission of CMV following non-primary maternal infections. This talk will highlight the global epidemiology of congenital CMV with particular emphasis on the disease burden in resource-poor settings.
Neonatal innate immunity to RSV: from pathogenesis to protection
Dr Mirjam Belderbos, University Medical Center Groningen, The Netherlands
Respiratory syncytial virus (RSV) is the leading cause of infant lower respiratory tract infection, accounting for 33.8 million episodes of acute respiratory tract infection and 66,000 – 199,000 deaths annually. Over 80% of severe RSV infections occur in otherwise healthy neonates and infants <6 months, urging for novel strategies to protect this vulnerable age group.
Toll-like receptor (TLR) responses play an essential role in the defence against RSV. Efficient viral clearance requires pathogen recognition through TLR4 and induction of a Th1-type immune response. In contrast, severe RSV disease is characterised by a Th2-type immune response, characterised by low levels of pro-inflammatory cytokines and high levels of IL-10. The distinct function of the neonatal TLR system, which is intrinsically biased against production of pro-inflammatory responses and favours production of IL-10, may predispose to severe RSV infection. This is supported by recent studies, which show that age-dependent differences in dendritic cells shape the immune response to RSV, and that neonatal dendritic cells require more co-stimulation than adult dendritic cells to induce protective responses.
The early postnatal period is essential for the development of the neonatal TLR system, and may provide a unique window of opportunity to prevent subsequent RSV bronchiolitis. For instance, environmental factors, such as breast feeding, presence of siblings and mode of delivery, have been shown to modulate postnatal TLR maturation. In addition, mechanistic studies have identified neonatal blood plasma as an important source of immune modulatory factors, which may provide novel targets to modulate neonatal innate responses and to optimise antiviral immunity.
This talk will discuss how insights into the neonatal innate immune system can be exploited to reduce the global burden of RSV infection.